Background: We examined the differential impact of a well-established human immunodeficiency virus (HIV)/sexually transmitted infections (STIs) curriculum, Be Proud! Be Responsible!, when taught by school nurses and health education classroom teachers within a high school curricula. Methods: Group-randomized intervention study of 1357 ninth and tenth grade students in 10 schools. Twenty-seven facilitators (6 nurses, 21 teachers) provided programming; nurse-led classrooms were randomly assigned. Results: Students taught by teachers were more likely to report their instructor to be prepared, comfortable with the material, and challenged them to think about their health than students taught by a school nurse. Both groups reported significant improvements in HIV/STI/condom knowledge immediately following the intervention, compared to controls. Yet, those taught by school nurses reported significant and sustained changes (up to 12 months after intervention) in attitudes, beliefs, and efficacy, whereas those taught by health education teachers reported far fewer changes, with sustained improvement in condom knowledge only. Conclusions: Both classroom teachers and school nurses are effective in conveying reproductive health information to high school students; however, teaching the technical (eg, condom use) and interpersonal (eg, negotiation) skills needed to reduce high-risk sexual behavior may require a unique set of skills and experiences that health education teachers may not typically have.